Abstract
Mitochondrial dysfunction promotes metabolic stress responses in a cell‐autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1‐TG) with compromised muscle‐specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1‐TG mice show a skeletal muscle‐specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1‐TG mice does not affect muscle wasting or transcriptional cell‐autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress‐induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15‐dependent daytime‐restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress‐induced GDF15 in the regulation of systemic energy metabolism.
Highlights
Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner
Using transgenic mice with compromised skeletal muscle-specific mitochondrial oxidative phosphorylation (OXPHOS) capacity via respiratory uncoupling (HSAUcp1-TG [TG]) [32,33], we explored the potential induction of growth differentiation factor 15 (GDF15) as a myokine (Fig 1A)
In line with the human skeletal actin (HSA)-driven skeletal muscle-specific UCP1 transgene [32], we found a strong induction of Gdf15 exclusively in skeletal muscles of TG mice, with the highest induction observed in mixed and predominantly fast-glycolytic fiber type muscle (EDL, tibialis anterior [TA], gastrocnemius [Gastroc], quadriceps [Quad]) and a lower induction in oxidative fiber type muscles (SOL, diaphragm, esophagus) of TG animals (Fig 1F and G)
Summary
Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1-TG) with compromised muscle-specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1-TG mice show a skeletal muscle-specific induction and diurnal variation of GDF15 as a myokine. Genetic loss of GDF15 in Ucp1-TG mice does not affect muscle wasting or transcriptional cell-autonomous stress response but promotes a progressive increase in body fat mass. Our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stressinduced GDF15 in the regulation of systemic energy metabolism
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